Anju Elizabeth Joham

Women with polycystic ovary syndrome have intrinsic insulin resistance on euglycaemic–hyperinsulaemic clamp

STUDY QUESTION What is the prevalence of insulin resistance (IR) and the contributions of intrinsic and extrinsic IR in women diagnosed with polycystic ovary syndrome (PCOS) according to the Rotterdam criteria? SUMMARY ANSWER We report novel clamp data in Rotterdam diagnosed PCOS women, using World Health Organization criteria for IR showing that women with PCOS have a high prevalence of IR, strengthening the evidence for an aetiological role of IR in both National Institutes of Health (NIH) and Rotterdam diagnosed PCOS in lean and overweight women. WHAT IS KNOWN ALREADY PCOS is a complex endocrine condition with a significant increased risk of gestational diabetes and type 2 diabetes. STUDY DESIGN, SIZE, DURATION Using a cross-sectional study design, 20 overweight and 20 lean PCOS (Rotterdam criteria), 14 overweight and 19 lean body mass index (BMI)-matched control non-PCOS women underwent clinical measures of IR after a 3-month withdrawal of insulin sensitizers and the oral contraceptive pill. MATERIALS, SETTING, METHODS In an academic clinic setting, glucose infusion rate (GIR) on euglycaemic-hyperinsulinaemic clamp was investigated as a marker of insulin sensitivity. MAIN RESULTS AND THE ROLE OF CHANCE PCOS women were more IR than BMI-matched controls (main effect for BMI and PCOS; P < 0.001). IR was present in 75% of lean PCOS, 62% of overweight controls and 95% of overweight PCOS. Lean controls (mean ± SD; GIR 339 ± 76 mg min⁻¹ m⁻²) were less IR than lean PCOS (270 ± 66 mg min⁻¹ m⁻²), overweight controls (264 ± 66 mg min⁻¹ m⁻²) and overweight PCOS (175 ± 96 mg min⁻¹ m⁻²). The negative relationship between BMI and IR reflected by GIR was more marked in PCOS (y = 445.1 - 7.7x, R² = 0.42 (P < 0.0001) than controls (y = 435.5 - 4.6x, R² = 0.04 (P < 0.01)). LIMITATIONS, REASONS FOR CAUTION The study did not use glucose tracer techniques to completely characterize the IR, as well as the lack of matching for body composition and age. WIDER IMPLICATIONS OF THE FINDINGS IR is exacerbated by increased BMI, supporting intrinsic IR in PCOS. BMI impact on IR is greater in PCOS, than in controls, irrespective of visceral fat, prioritizing lifestyle intervention and the need for effective therapeutic interventions to address intrinsic IR and prevent diabetes in this high-risk population. STUDY FUNDING/COMPETING INTEREST(S) This investigator-initiated trial was supported by grants from the National Health & Medical Research Council (NHMRC) Grant number 606553 (H.J.T., N.K.S. and S.K.H.) as well as Monash University and The Jean Hailes Foundation. H.J.T. is an NHMRC Research Fellow. N.K.S. is supported through the Australian Governments Collaborative Research Networks (CRN) programme. A.E.J. is a Jean Hailes and NHMRC scholarship holder. The authors declare that there is no conflict of interest associated with this manuscript.

Longitudinal weight gain in women identified with polycystic ovary syndrome: results of an observational study in young women.

Polycystic ovary syndrome (PCOS) affects 6‐18% of women. The natural history of weight gain in women with PCOS has not been well described. Here we aimed to examine longitudinal weight gain in women with and without PCOS and to assess the association between obesity and PCOS prevalence.

Gestational Diabetes and Type 2 Diabetes in Reproductive-Aged Women With Polycystic Ovary Syndrome

CONTEXT Polycystic ovary syndrome (PCOS) affects 6%-21% of women. PCOS has been associated with an increased risk of dysglycemia including gestational diabetes mellitus (GDM) and type 2 diabetes mellitus (T2DM). OBJECTIVE The objective of the study was to assess the prevalence of dysglycemia and the impact of obesity in young reproductive-aged women with and without PCOS in a community-based cohort. DESIGN This was a cross-sectional analysis of data from a large longitudinal study (the Australian Longitudinal Study on Womens Health). SETTING The setting for the study was the general community. PARTICIPANTS Women were randomly selected from the national health insurance database. Standardized data collection occurred at five survey time points (years 1996, 2000, 2003, 2006, and 2009). Data from survey 4 (2006, n = 9145, 62% of original cohort aged 18-23 y) were examined for this study. MAIN OUTCOME MEASURES Self-reported PCOS, GDM, and T2DM were measured. RESULTS In women aged 28-33 years, PCOS prevalence was 5.8% [95% confidence interval (CI) 5.3%-6.4%]. The prevalence of GDM (in women reporting prior pregnancy) and T2DM was 11.2% and 5.1% in women with PCOS and 3.8% and 0.3% in women without PCOS, respectively (P for both < .001). PCOS was associated with an increased odds of GDM and T2DM. After adjusting for age, body mass index, hypertension, smoking, and demographic factors, the odds of GDM (odds ratio 2.1, 95% CI 1.1-3.9, P = .02) and T2DM (odds ratio 8.8, 95% CI 3.9-20.1, P < .001) remained increased in women reporting PCOS. CONCLUSIONS In a large community-based cohort of reproductive-aged women, PCOS was independently associated with a higher risk of GDM and T2DM, independent of body mass index. Aggressive screening, prevention, and management of dysglycemia is clearly warranted in women with PCOS.

Prevalence of Infertility and Use of Fertility Treatment in Women with Polycystic Ovary Syndrome: Data from a Large Community-Based Cohort Study

BACKGROUND Polycystic ovary syndrome (PCOS) affects 6%-21% of women. PCOS is the primary cause of anovulatory infertility, with major health and economic costs, yet we are unaware of any community-based, natural history studies on fertility and fertility treatments published to date. We aim to compare infertility, fertility treatment use, and relationship to body mass index (BMI) in women reporting PCOS to women not reporting PCOS in a community-based population. METHODS This is a cross-sectional analysis of a longitudinal cohort study, the Australian Longitudinal Study on Womens Health (ALSWH). For the ALSWH, women from the general community were randomly selected from the national public insurance database. Mailed survey data were collected at multiple time points. At survey 4, there were 9145 respondents aged 28-33 years. Of 8612 women with known PCOS status, 478 women reported having PCOS. Information regarding fertility status was available for 4856 women. This was the subgroup used in this analysis. The main outcomes measures are self-reported PCOS status, BMI, infertility, and use of fertility therapies including ovulation induction and in vitro fertilization (IVF). Logistic regression was used to examine factors associated with infertility and use of fertility treatment. RESULTS Self-reported PCOS prevalence was 5.8% (95% confidence interval [CI]: 5.3%-6.4%). Infertility was noted by 72% of 309 women reporting PCOS, compared with 16% of 4547 women not reporting PCOS (p<0.001). Infertility was 15-fold higher in women reporting PCOS (adjusted odds ratio 14.9, 95% CI 10.9-20.3), independent of BMI. Of women reporting infertility, there was greater use of fertility hormone treatment, (62%, n=116 vs. 33%, n=162, p<0.001) in women reporting PCOS; however, IVF use was similar. CONCLUSIONS In this community-based cohort of women, infertility and use of fertility hormone treatment was significantly higher in women reporting PCOS. Considering the prevalence of PCOS and the health and economic burden of infertility, strategies to optimize fertility are important.

Contraception use and pregnancy outcomes in women with polycystic ovary syndrome: data from the Australian Longitudinal Study on Women's Health

STUDY QUESTION Do contraception use, pregnancy outcome and number of children differ in women with and without polycystic ovary syndrome (PCOS)? SUMMARY ANSWER Women with PCOS were less likely to report use of contraception and more likely to report a miscarriage, whilst number of children was similar between groups. WHAT IS KNOWN ALREADY The oral contraceptive pill is used in the management of PCOS, but the patterns of contraception use in women with PCOS is not known. In women with PCOS who undergo assisted reproduction, the risk of pregnancy loss appears higher, yet pregnancy loss and family size among community-based women with PCOS is not known. STUDY DESIGN, SIZE AND DURATION This is a cross-sectional analysis of a longitudinal cohort study. Mailed survey data were collected at five time points (years 1996, 2000, 2003, 2006 and 2009). Data from respondents to Survey 4 (2006), aged 28-33 (n = 9145, 62% of the original cohort aged 18-23 years) were analysed. PARTICIPANTS/MATERIALS, SETTING, METHODS This study was conducted in a general community setting. Data from participants who responded to the questions on PCOS, contraception and pregnancy outcome were analysed. The main outcome measures were self-reported PCOS, body mass index (BMI), contraception use, pregnancy loss and number of children. MAIN RESULTS AND THE ROLE OF CHANCE In women aged 28-33 years, women with PCOS were less likely to be using contraception (61 versus 79%, P < 0.001) and more likely to be trying to conceive (56 versus 45%, P < 0.001), compared with women not reporting PCOS. A greater proportion of women with PCOS reported pregnancy loss (20 versus 15%, P = 0.003). PCOS was not independently associated with pregnancy loss; however, BMI was independently associated with pregnancy loss in the overweight and obese groups (OR 1.2, 95% CI 1.04-1.4, P = 0.02 and OR 1.4, 95% CI 1.1-1.6, P = 0.001, respectively). Fertility treatment use was also independently associated with pregnancy loss (adjusted OR 3.2, 95% CI 2.4-4.2, P < 0.001). There was no significant difference in number of children between women with and without PCOS. LIMITATIONS, REASON FOR CAUTION PCOS, contraception use and pregnancy outcome data were self-reported. Attrition occurred, but is reasonable compared with similar longitudinal cohort studies. WIDER IMPLICATIONS OF THE FINDINGS This community-based cohort aged 28-33 years provides insights into the contraceptive use, pregnancy loss and family size of a large cohort of unselected women. Women reporting PCOS had lower rates of contraception use and were more likely to be currently trying to conceive, suggesting that they may be aware of potential fertility challenges, yet in those not planning to conceive, contraceptive use was low and further education may be required. Despite prior reports of higher rates of pregnancy loss in PCOS, usually from infertility services, in this community-based population, PCOS was not independently associated with pregnancy loss, yet independent risk factors for pregnancy loss included higher BMI, were higher in PCOS. The number of children per woman was similar in the both groups, albeit with more infertility treatment in PCOS. This may reassure women with PCOS that with access to fertility treatment, family sizes appear similar to women not reporting PCOS.

Polycystic ovary syndrome and anti‐Müllerian hormone: role of insulin resistance, androgens, obesity and gonadotrophins

Polycystic ovary syndrome (PCOS) is a complex endocrine disorder associated with insulin resistance, hyperandrogenism, obesity, altered gonadotrophin release and anovulatory infertility. Anti‐Müllerian hormone (AMH) has been proposed as a marker of ovarian function and fertility. Across a cohort of lean and overweight women with and without PCOS, we investigated the association of AMH with insulin resistance and body composition using gold standard measures. A secondary aim was to examine whether AMH was useful to determine PCOS status.

Biomarkers and insulin sensitivity in women with Polycystic Ovary Syndrome: Characteristics and predictive capacity

Polycystic ovary syndrome (PCOS) is a common endocrine disorder associated with metabolic complications. Metabolic biomarkers with roles in obesity, glycaemic control and lipid metabolism are potentially relevant in PCOS. The aim was to investigate metabolic biomarkers in lean and overweight women with and without PCOS and to determine whether any biomarker was able to predict insulin resistance in PCOS.

Pigment Epithelium‐Derived Factor, Insulin Sensitivity, and Adiposity in Polycystic Ovary Syndrome: Impact of Exercise Training

Pigment epithelium‐derived factor (PEDF) is upregulated in obese rodents and is involved in the development of insulin resistance (IR). We aim to explore the relationships between PEDF, adiposity, insulin sensitivity, and cardiovascular risk factors in obese women with polycystic ovary syndrome (PCOS) and weight‐matched controls and to examine the impact of endurance exercise training on PEDF. This prospective cohort intervention study was based at a tertiary medical center. Twenty obese PCOS women and 14 non‐PCOS weight‐matched women were studied at baseline. PEDF, cardiometabolic markers, detailed body composition, and euglycemic—hyperinsulinemic clamps were performed and measures were repeated in 10 PCOS and 8 non‐PCOS women following 12 weeks of intensified aerobic exercise. Mean glucose infusion rate (GIR) was 31.7% lower (P = 0.02) in PCOS compared to controls (175.6 ± 96.3 and 257.2 ± 64.3 mg.m−2.min−1) at baseline, yet both PEDF and BMI were similar between groups. PEDF negatively correlated to GIR (r = −0.41, P = 0.03) and high‐density lipoprotein (HDL) (r = −0.46, P = 0.01), and positively to cardiovascular risk factors, systolic (r = 0.41, P = 0.02) and diastolic blood pressure (r = 0.47, P = 0.01) and triglycerides (r = 0.49, P = 0.004). The correlation with GIR was not significant after adjusting for fat mass (P = 0.07). Exercise training maintained BMI and increased GIR in both groups; however, plasma PEDF was unchanged. In summary, PEDF is not elevated in PCOS, is not associated with IR when adjusted for fat mass, and is not reduced by endurance exercise training despite improved insulin sensitivity. PEDF was associated with cardiovascular risk factors, suggesting PEDF may be a marker of cardiovascular risk status.

Hypertension in Reproductive-Aged Women With Polycystic Ovary Syndrome and Association With Obesity.

BACKGROUND Polycystic ovary syndrome (PCOS) is a common disorder with metabolic complications, yet the prevalence of hypertension is unclear. We aim to assess hypertension prevalence and the impact of obesity in women reporting PCOS compared to those not reporting PCOS. METHODS This is a cross-sectional analysis of data from a large longitudinal study, the Australian Longitudinal Study on Womens Health (ALSWH). Women from the general community were randomly selected from the national health insurance database. Standardized data collection occurred at 6 survey time points. Data from Survey 4 in 2006 (n = 8,612, age: 28-33 years) were examined for this study. The main outcome measures studied were self-reported PCOS and hypertension. RESULTS Reported PCOS prevalence was 5.8% (95% confidence interval (CI): 5.3%-6.4%). Women with PCOS had higher body mass index (BMI). Hypertension prevalence was 5.5% (95% CI: 3.3-7.7) in women reporting PCOS and 2.0% (95% CI: 1.6-2.3) in women not reporting PCOS (P < 0.001). Hypertension was associated with BMI (odds ratio: 1.07, 95% CI: 1.05-1.10, P < 0.001) with a trend towards an association with PCOS (P = 0.09). On subgroup analysis, hypertension was not associated with BMI in women reporting PCOS but was associated in those not reporting PCOS. CONCLUSIONS In this large community-based cohort, we note increased prevalence of hypertension and higher BMI in young women reporting PCOS. BMI association with hypertension appeared clear in women not reporting PCOS. Yet in women with PCOS, hypertension appeared to not be associated with BMI, akin to observations on diabetes risk in PCOS, suggesting that metabolic abnormalities in PCOS may be independent of BMI.

Polycystic Ovary Syndrome, Obesity, and Pregnancy

Polycystic ovary syndrome (PCOS) is a common endocrine disorder affecting up to one in five reproductive-aged women. It is underpinned by insulin resistance and hyperandrogenism and is associated with metabolic, reproductive, and psychological features. Women with PCOS have higher rates of obesity and central adiposity compared with women without PCOS, and weight strongly influences prevalence and clinical severity of PCOS. Women with PCOS may have subfertility and women should be aware of factors affecting fertility, in particular the impact of obesity and age. Once pregnant, women with PCOS have significantly increased risk of pregnancy-related complications including gestational diabetes, hypertensive disorders, premature delivery, and delivery by cesarean section. The offspring of women with PCOS may have increased risk of congenital abnormalities and hospitalization in childhood. Clinicians should be aware of the increased risk and screen, prevent, and manage accordingly.